Behavior Genetics

The classical twin model can be reparametrized as an equivalent multilevel model. The multilevel parameterization has underexplored advantages, such as the possibility to include higher-level clustering variables in which lower levels are nested. When this higher-level clustering is not modeled, its variance is captured by the common environmental variance component. In this paper we illustrate the application of a 3-level multilevel model to twin data by analyzing the regional clustering of 7-year-old children’s height in the Netherlands. Our findings show that 1.8%, of the phenotypic variance in children’s height is attributable to regional clustering, which is 7% of the variance explained by between-family or common environmental components. Since regional clustering may represent ancestry, we also investigate the effect of region after correcting for genetic principal components, in a subsample of participants with genome-wide SNP data. After correction, region no longer explained variation in height. Our results suggest that the phenotypic variance explained by region might represent ancestry effects on height.

This study introduces and illustrates the potential of an integrated multi-omics approach in investigating the underlying biology of complex traits such as childhood aggressive behavior. In 645 twins (cases = 42%), we trained single- and integrative multi-omics models to identify biomarkers for subclinical aggression and investigated the connections among these biomarkers. Our data comprised transmitted and two non-transmitted polygenic scores (PGSs) for 15 traits, 78,772 CpGs, and 90 metabolites. The single-omics models selected 31 PGSs, 1614 CpGs, and 90 metabolites, and the multi-omics model comprised 44 PGSs, 746 CpGs, and 90 metabolites. The predictive accuracy for these models in the test (N = 277, cases = 42%) and independent clinical data (N = 142, cases = 45%) ranged from 43 to 57%. We observed strong connections between DNA methylation, amino acids, and parental non-transmitted PGSs for ADHD, Autism Spectrum Disorder, intelligence, smoking initiation, and self-reported health. Aggression-related omics traits link to known and novel risk factors, including inflammation, carcinogens, and smoking.

This study introduces a novel approach to the dissection of polygenic variation. First, multidimensional analysis was used to define groups within the normal population. Next, these groups were compared on behavioral and physiological measures to establish underlying mechanisms. Finally, groups were compared on a range of polymorphic markers to determine the extent of single-gene effects. As this approach was conducted using three ethnic populations, the implications of between-, as well as within-, population variation can be assessed.

Complex illnesses, like depression, are thought to arise from the interplay between psychosocial stressors and genetic predispositions. Approaches that take into account both personal and neighborhood factors and that consider gene regions as well as individual SNPs may be necessary to capture these interactions across race and ethnic groups. We used novel gene-region based analysis methods [Sequence Kernel Association Test (SKAT) and meta-analysis (MetaSKAT), gene-environment set association test (GESAT)], as well as traditional linear models to identify gene region and SNP × psychosocial factor interactions at the individual- and neighborhood-level, across multiple race/ethnicities. Multiple regions identified in SKAT analyses showed evidence of a significant gene-region association with averaged depressive symptom scores across race/ethnicity (MetaSKAT p values <0.001). One region × neighborhood-environment interaction was significantly associated with averaged depressive symptom score across race/ethnicity after multiple testing correction (chr 18:21454070-21494070, Fisher’s combined p value = 0.001). The examination of gene regions jointly with environmental factors measured at multiple levels (individuals and their contexts) may shed light on the etiology of depressive illness across race/ethnicities.

The genetic basis of larval locomotor activity inDrosophila melanogaster was studied by comparing four strains that differ significantly in activity levels. The inbred wild-type strain Canton-S had the lowest activity level, while the relatively heterogeneous wild-type OK1 genotype had the highest. Activities could not be explained simply in terms of a difference in catecholamine levels. The analysis of heterozygous whole-chromosome effects suggested that chromosome 2 carried modifiers that increased activity, but an interchromosomal interaction balanced its effect in OK1. A sex-limited interaction countering an X-chromosome effect in Canton-S was also consistent with the conclusion that stabilizing interactions are an important part of the genetic control of this behavioral phenotype.

Ultrasonic calls produced by young mice elicit maternal investigation and retrieval, and their characteristics have been shown to vary with age and genotype. In this study, we completed a full Mendelian cross of two inbred strains BALB/cJ and DBA/2J. The major result was the detection of directional dominance for a high rate of calling. Other characteristics were influenced by additive and maternal effects in the absence of directional dominance. We estimate the number of loci involved in the rate of calling to be about 1—facilitating studies of a gene-to-behavior pathway.

Latent inhibition (LI) is the retardation of associative conditioning resulting from preexposure of the conditioned stimulus (CS) alone prior to conditioning. Schizophrenic patients show deficient prepulse inhibition (PPI) and, at least acutely, deficient LI as well. We recently found that Brown Norway (BN) rats show a PPI deficit compared to Wistar-Kyoto (WKY) rats. If PPI and LI depend on neural processes with common genetic substrates, then LI should be deficient in BN rats as well. Here, LI of a conditioned taste aversion was examined in BN and WKY rats. One group from each strain was preexposed to a saccharin-flavored solution (CS) the day prior to conditioning. For taste aversion conditioning, these two groups again consumed saccharin and were injected with lithium chloride (unconditioned stimulus) 10 min later. A second group from each strain was not preexposed to the CS and was treated identically during conditioning, while a third group was not conditioned (injected with sodium chloride). To test for taste aversion conditioning, saccharin was offered for 20 min/day for 3 days. Nonconditioned BN and WKY rats consumed equal amounts of saccharin on test days. In both strains, conditioned rats showed a saccharin aversion. However, conditioning was less robust in BN than in WKY rats. WKY rats showed good LI of the conditioned taste aversion in that preexposed WKY rats consumed significantly more saccharin on test days than conditioned, nonpreexposed WKY rats. Preexposed BN rats did not consume significantly more saccharin on test days than conditioned, nonpreexposed BN rats. The previously reported deficiency in PPI in the BN rats was confirmed here 1 week after the taste aversion experiment. These results suggest that BN rats show deficient LI as well as PPI and display poor associative learning, a trait also reported in schizophrenia.

Genetic variations in the adrenergic receptor (ADR) have been associated with body composition in cross-sectional studies. Recent findings suggest that ADR variants may also modify body composition response to lifestyle. We assessed the role of ADR variants in body composition response to 12 months of resistance training versus control in previously sedentary postmenopausal women. Randomized trial completers were genotyped for A2B Glu9/12 by fragment length analysis, and B2 Gln27Glu and B3 Trp64Arg by TaqMan (n = 148, 54% hormone therapy users). Associations between genotypes and body composition, by dual energy X-ray absorptiometry, were analyzed using univariate models. There was no main effect of individual genes on change in body composition, however, gene × exercise interactions were observed for A2B Glu9/12 and B2 Gln27Glu on change in lean soft tissue (LST, p = 0.02); exercisers on the A2B Glu9− background gained LST compared to a loss among controls over 12 months (p < 0.05), with no significant intervention effect on the A2B Glu9+ background. Similarly, there was a significant LST gain with exercise on the B2 Glu27+ background compared to loss among controls and no intervention effect on the B2 Glu27− background. A non-significant association between total body fat (TBF) and B3 Trp64Arg persisted among sedentary controls only when intervention groups were separated (%TBF gain with B3 Arg64+ carriage, p = 0.03); exercisers lost TBF regardless of genotype. In summary, effect modification by lifestyle was demonstrated on ADRA2B, B2, and B3 genetic backgrounds. Individuals with certain ADR genotypes may be more vulnerable to adverse changes in body composition with sedentary behavior, thus these candidate genes warrant further study.